Patients with Type 2 diabetes (T2DM) have microvascular insulin resistance and dysfunction; both contribute to metabolic insulin resistance and cardiovascular complications. Glucagon-like peptide 1 (GLP-1) potently recruits muscle microvasculature and increases muscle delivery and action of insulin, likely via a protein kinase A and nitric oxide dependent pathway in laboratory animals. In the proposed studies, we will test an overarching hypothesis that sustained activation of the GLP-1 receptor (GLP-1R) enhances muscle microvascular perfusion, promotes angiogenesis, and improves the muscle microvascular response to insulin which leads to increased muscle insulin delivery and action in diabetes. We will examine whether sustained GLP- 1R activation will 1) in healthy humans increase basal muscle microvascular perfusion and rescues muscle microvascular and metabolic insulin responses in the setting of acute lipid-induced insulin resistance; 2) restore muscle microvascular insulin sensitivity, improve muscle capillarization and enhance muscle insulin delivery and action in patients with chronic insulin resistance as seen in pre-diabetes or T2DM; and 3) prevent microvascular insulin resistance, enhance trans-endothelial insulin transport and promotes muscle angiogenesis via an AMPK-mediated pathway in high fat diet (HFD) fed rats. We will use a state-of-the-art technique, contrast-enhanced ultrasound, in combination with forearm arteriovenous balance, muscle biopsy and insulin clamp to quantify the effects of sustained GLP-1R activation on microvascular and metabolic responses to insulin in humans with or without insulin resistance/diabetes and open a new avenue for future mechanistic and/or therapeutic studies. We will further in animal studies explore the underlying mechanisms. By understanding the regulation of muscle microcirculation, it may be possible to correct vascular and ameliorate metabolic insulin resistance and decrease the cardiovascular morbidity and mortality associated with diabetes.